Nasal carriage of Staphylococcus aureus is a predisposing factor to iatrogenic infections and an important means of harboring and spreading resistant strains. The disorder affects 20-30% of apparently healthy people, but its molecular basis is unknown. In preliminary studies, we characterized the antibacterial properties of nasal mucus and obtained evidence that the nasal mucus of carriers (but not non-carriers) is permissive for the growth of Staphylococcus aureus. In addition, we obtained evidence that the carriage of S. aureus induces inflammation characterized by neutrophil influx and increased production of the epithelial beta-defensin, HBD-2. Further study of this disorder is important not only because of its medical implications but also because it represents an accessible model of the interaction of bacteria with a mucosal surface. We propose four specific aims to develop this model and to begin the search for the underlying defect in mucosal immunity: (1) identify the specific topographic areas of the nasal mucosa in which S. aureus is carried; (2) characterize the differences in mucus composition, anti-S. aureus activity and inflammatory response between non-carriers, sporadic carriers and persistent nasal carriers of S. aureus; (3) in preparation for a search for human S. aureus-carriage genes, perform family studies of S. aureus carriage to estimate the shared environmental and genetic component of this condition; and (4) develop a differential display/gene array approach to screen for genes differentially expressed on involved nasal surfaces of transient carriers during carriage versus noncarriage and persistent carriers versus persistent noncarriers. These studies aim to provide the information necessary for more rapid advances in studies of mucosal resistance to colonization, and will attempt to develop a useful natural model for the study of the interactions of bacteria with an accessible mucosal surface.